Abstract

1882

BRCA1 and BRCA2 are the two major genes implicated in breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, irrespectively of the mutation detection method employed, the percentage of families without identifiable molecular alterations of the two genes is still higher than 50 %, even when stringent criteria are used for family selection. A small but significant increase in mutation detection rate has been contributed by the discovery of large genomic alterations in the BRCA1 gene that were previously missed by most of the point mutation detection approaches. Although a precise figure of the worldwide prevalence of these alterations is still lacking, it is now clear that analysis of BRCA1 genomic rearrangements should be routinely performed to maximize the accuracy of mutational screening. A few studies have addressed the question of whether BRCA2 might be inactivated by similar alterations in a significant number of families; most were performed on unselected sets of samples and/or employed cumbersome mutation detection methods of variable sensitivity. Therefore, the percentage of predisposed families with BRCA2 rearrangements remains to be determined. To approach this question, we recently analysed 132 highly selected families using the BRCA2 Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Three different genomic rearrangements were identified and confirmed by analysis of the mutant transcript and genomic characterization of the breakpoints. Thus, in our hands, genomic rearrangements represent 11% (3/27) of the BRCA2 mutational spectrum. We conclude that, in contrast to previous suggestions, the presence of BRCA2 genomic rearrangements merits investigation in high risk breast and/or ovarian cancer families.